H2020Индивидуална стипендия2021–2023

CENTEL · Deciphering the mechanisms of developmentally regulated centriole elimination

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-04-01 → 2023-03-31
Финансиране от ЕС: 191 149 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите за премахване на центриолите при образуването на яйцеклетки се изучават чрез наблюдение на червея C. elegans. Разбирането на този процес помага да се разберат причините за развитието на рак и неврологични заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Deciphering the mechanisms of developmentally regulated centriole elimination

Introduction: Centrioles are conserved, membrane-less organelles, which exhibit a 9-fold radial arrangement of microtubules (MTs). Centrioles seed the formation of cilia and flagella and organize the centrosome. The number of centrioles in a cell determines the number of cilia, flagella and centrosomes. Therefore, controlling centriole number is essential for the correct function of several cellular processes. Failure in centriole numbers control is linked to detrimental health outcome, including e.g. cancer and neuro-pathologies. In proliferating cells, centriole number control is linked to the cell cycle. However, during sexual reproduction centrioles must be eliminated from the oocyte to ensure that the zygote inherits only two centrioles from the sperm. Despite the fact that centriole elimination during oogenesis is an essential and widely applied process, the mechanisms governing it remain largely elusive. In this project, we have used the round worm C. elegans to investigate the mechanisms that govern centriole elimination during oogenesis. The gonad of the worm is ideally suited to this end since it provides a pseudo time-course of oogenesis. Nuclei are generated in the proliferating stem cell niche located at the distal end of the gonad, and then progress through the remainder of the gonad, undergoing consecutive stages of meiotic prophase I, followed by cellularization and progressive maturation of oocytes (Fig 1). Centrioles are eliminated during this oogenesis, resulting in mature oocytes without centrioles. The worm centriole provides the additional advantage that, unlike the human centriole, for instance, it is thought to comprise only a dozen different types of core proteins, which are evolutionarily conserved. However, how exactly these components build the stereotyped centriole architecture and whether this is altered over the course of oogenesis elimination was not known. The research carried out under this project resulted in a detailed description of the centriolar architecture before and during the elimination process. We found that the proteasome acts directly on the centriole during elimination. Our data suggest that proteasome activity is regulated and timely constrained by specific centriolar architecture and alteration thereof. The process seems to be mechanistically conserved from protists to animals.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Centrioles are evolutionary conserved organelles that template the formation of cilia, flagella and centrosomes. Centriole number dictates how many such structures form in a cell, so that controlling this number is essential for proper development and health. During sexual reproduction of animals, only the sperm contributes centrioles to the zygote, whereas centrioles are eliminated from the oocyte. The signals initiating and the processes executing centriole elimination remain largely elusive, both during oogenesis and in other developmental contexts where this can occur. Here, I propose to conduct state-of-the art live imaging and use novel quantitative super-resolution approaches in C. elegans to uncover the timing and molecular changes during oogenesis centriole elimination. Moreover, I will decipher the role of the RNA-binding protein CGH-1 in the timing of centriole elimination through a sequencing-based approach. Furthermore, I will conduct a proteomic screen to identify and characterize novel components required for oogenesis centriole elimination in worms. In a complementary approach, I will address the potential evolutionary conservation of centriole elimination mechanisms using the protist N. gruberi, which diverged from C. elegans over a billion years ago. I propose to also analyze in detail the dynamics of the elimination process in this system using deployed molecular markers. Moreover, I will conduct a proteomic screen to identify candidate centriolar proteins directing centriole elimination in N. gruberi. Furthermore, I will develop RNAi-mediated and CRISPR/Cas9 inactivation methods to test the function of candidate proteins in centriole elimination, thus also adding an important item to the toolbox at the disposal of scientists using N. gruberi. Overall, my work is expected to reveal whether centriole elimination is an ancestral mechanisms that has been conserved across eukaryotes and uncover the underlying molecular tenets of this process.

Оригинален текст от CORDIS (на английски).

Участници

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE · LausanneКоординаторШвейцария